Circulating molecules reflect imaging biomarkers of hemorrhage in cerebral cavernous malformations.

Increases in mean lesional iron content by quantitative susceptibility mapping (QSM) by ≥6% and/or vascular permeability by dynamic contrast enhanced quantitative perfusion (DCEQP) by ≥40% on MRI have been associated with new symptomatic hemorrhage (SH) in cerebral cavernous malformations (CCMs). It is not known if plasma biomarkers can reflect these changes within the lesion proper. This cohort study enrolled 46 CCM patients with SH in the prior year. Plasma samples, QSM and DCEQP were simultaneously acquired at the beginning and end of 60 one-year epochs of prospective follow-up. Plasma levels of 16 proteins and 12 metabolites linked to CCM hemorrhage were assessed by enzyme-linked immunosorbent assay and liquid-chromatography mass spectrometry, respectively. A weighted model combining the percent changes in plasma levels in roundabout guidance receptor-4, cluster of differentiation 14, thrombomodulin and acetyl-L-carnitine reflected a mean increase in QSM ≥ 6% (97.2% and 100% specificity/sensitivity, p = 3.1 × 10^-13). A weighted combination of percent changes in plasma levels of endoglin, pipecolic acid, arachidonic acid and hypoxanthine correlated with an increase in mean DCEQP ≥40% (99.6% specificity and 100% sensitivity, p = 4.1 × 10^-17). This is a first report linking with great accuracy changes of circulating molecules to imaging changes reflecting new SH during prospective follow-up of CCMs.